Substituted 2,3-dihydrobenzofuran compounds and their use as synergists

ABSTRACT

The invention relates to a compound of Formula (I), wherein n is 0 or 1, R 1  is H or CH 3  and R 2  is a linear (C 3 -C 6 )alkyl and an insecticide composition comprising at least one insecticide active ingredient and at least one a compound of Formula (I).

This application is a U.S. national stage of PCT/EP2016/071018 filed on7 Sep. 2016, which claims priority to and the benefit of EuropeanApplication No. 15184406.5 filed on 9 Sep. 2015, the contents of whichare incorporated herein by reference in their entireties.

FIELD OF INVENTION

The invention concerns substituted 2,3-dihydrobenzofuran compounds andtheir uses as synergists of insecticide active ingredients.

The work leading to this invention has received funding from theEuropean Union Seventh Framework Programme (FP7/2007-2013) under grantagreement n.605740

STATE OF THE ART

Compounds which are no toxic or only slightly toxic against insects, butin combination with active ingredients can produce a new insecticide,having an effectiveness significantly greater than the sum of thecomponents when used separately, are named synergists.

These compounds may in principle act in several ways, but one the mainmechanism is reported by interacting with the metabolism of the activesubstance. Metabolism can proceed through oxidative, hydrolytic,conjugative and absorption reactions and possible variations thereof.

On the basis of the discovery of synergists and of their mode ofactions, a wide range research and development started from the mid 50′giving products interesting for scientific research, but only a few formarket purposes.

One of the most effective and widely used synergists is represented bypiperonyl butoxide(5-[2-(2-butoxyethoxy)ethoxymethyl]-6-propyl-1,3-benzodioxole) claimedin U.S. Pat. No. 2,550,737.

Piperonyl butoxide is claimed to give a synergistic effect incombination with pyrethrins as well as pyrethroids such as allethrin,prallethrin, tetramethrin and so on.

In László Pap et al., “Comparative evaluation of new synergistscontaining a butynyl-type synergophore group and piperonyl butoxidederivatives”, Pest Management Sci., 57, 186-190, (2001) the synergisticactivity of substituted methylenedioxyphenyl derivatives and substituteddimethoxybenzene derivatives is studied and the 2-butynyloxymethyl groupis suggested as a synergophore group, particularly for dimethoxybenzenestructure, in combination with carbofuran insecticide.

In U.S. Pat. No. 8,809,389 a composition comprising an alkynyl phenoxycompound as a synergist compound and a pesticidal active ingredient isdescribed. This patent describes the preparation, in Example 11, of6-(but-2-ynyloxy)-5-propyl-2,3-dihydrobenzofuran, which is not tested assynergist compound.

In Despina Phillippou et al “The interactions between piperonyl butoxideand E4, a resistance-associated esterase from the peach-potato aphid,Myzus persicae Sulzer (Hemiptera:Aphididae)”, Pest Mang. Sci, 2013,69(4), 499-506, 6-(but-2-ynyloxy)-2,3-dihydrobenzofuran was described(compound EN16-18) and its binding affinity was evaluated and comparablewith PBO.

While these derivatives have shown synergistic activity with some activeingredients, it is still felt a great need for new synergisticcompounds, that in combination with active ingredients show a betterinsecticide activity than the compounds of the prior art.

SUMMARY OF THE INVENTION

The above object has been achieved by a compound of Formula (I)

-   wherein n is 0 or 1,-   R₁ is H or CH₃ and-   R₂ is a linear (C₃-C₆)alkyl.

The inventors of the present invention surprisingly found out that analkynyl group in the 2,3-dihydrobenzofuran structure confers synergisticactivity when combined with the specific linear alkyl chain of 3-6carbon atoms. Specifically, the selection and the positions of the twosubstituents in the 2,3-dihyrobenzofuran structure as per Formula (I)gave unexpected synergistic properties as it will be evident from theexperimental part.

Without being bound to any theory the inventors deem that the twospecific substituents in positions 5 and 7 of the 2,3-dihydrobenzofuranstructure as well as the length of the alkyl chain can interact with theblockade of the enzymes, by a modulation of the binding affinity withthe enzymes.

In another aspect the invention relates hence to the use of substituted2,3-dihydrobenzofuran compounds of Formula (I) as synergistic compoundsof insecticidal active ingredients.

In another aspect the invention relates to an insecticidal compositioncomprising at least one insecticidal active ingredient and at least onesubstituted 2,3-dihydrobenzofuran compound of Formula (I)

-   wherein n is 0 or 1,-   R₁ is H or CH₃ and-   R₂ is a linear (C₃-C₆)alkyl.

Under a further aspect, the invention relates to the following specificcompounds:

5-n-hexyl-7-((prop-2-ynyloxy)methyl)-2,3-dihydrobenzofuran

a compound of formula (I) wherein n is 1, R₁ is H, and R₂ is an n-hexylsubstituent;

5-n-hexyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran

a compound of formula (I) wherein n is 1, R₁ is CH₃, and R₂ is ann-hexyl substituent;

5-n-butyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran

a compound of formula (I) wherein n is 1, R₁ is CH₃, and R₂ is a butylsubstituent;

5-n-hexyl-7-(but-2-ynyloxy)-2,3-dihydrobenzofuran,

a compound of formula (I) wherein n is 0, R₁ is CH₃, and R₂ is ann-hexyl substituent;

5-n-butyl-7-((prop-2-ynyloxy)methyl)-2,3-dihydrobenzofuran

a compound of formula (I) wherein n is 1, R₁ is H, and R₂ is an n-butylsubstituent;

5-n-hexyl-7-(prop-2-ynyloxy)-2,3-dihydrobenzofuran

a compound of formula(I) wherein n is 0, R₁ is H, and R₂ is an n-butylsubstituent;

5-n-propyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran

a compound of formula (I) wherein n is 1, R₁ is CH₃, and R₂ is an-propyl substituent;

5-n-propyl-7-((prop-2-ynyloxy)methyl)-2,3-dihydrobenzofuran

a compound of formula(I) wherein n is 1, R₁ is H, and R₂ is a n-propylsubstituent;

In yet a further aspect of the invention, the invention relates to theuse of the insecticide composition as insecticide.

In yet a further aspect of the invention, the invention relates to theinsecticide composition of the invention for use in veterinary medicine.

In yet a further aspect of the invention, the invention relates to theinsecticide composition for use in treating pediculosis in humans.

DETAILED DESCRIPTION OF THE INVENTION

The present invention concerns a compound of Formula (I)

-   wherein n is 0 or 1,-   R₁ is H or CH₃ and-   R₂ is a linear (C₃-C₆)alkyl.

Preferably n is 1 and, more preferably R₂ is n-butyl or n-hexyl.

Still more preferably the compound of Formula (I) is one of:

5-n-hexyl-7-((prop-2-ynyloxy)methyl)-2,3-dihydrobenzofuran),

a compound of formula (I) wherein n is 1, R₁ is H, and R₂ is an n-hexylsubstituent, having Chemical Formula C₁₈H₂₄O₂ and Molecular Weight (MW)of 272.38 Dalton whose structure is confirmed by ¹H and ¹³C NMRanalyses;

5-n-hexyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran,

a compound of formula (I) wherein n is 1, R₁ is CH₃, and R₂ is ann-hexyl substituent having Chemical Formula C₁₉H₂₆O₂ and MolecularWeight (MW) of 286.41 Dalton whose structure is confirmed by ¹H and ¹³CNMR analyses;

5-n-butyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran,

a compound of formula (I) wherein n is 1, R₁ is CH₃, and R₂ is a butylsubstituent having Chemical Formula C₁₇H₂₂O₂ and Molecular Weight (MW)of 258.36 Dalton whose structure is confirmed by ¹H and ¹³C NMRanalyses;

5-n-hexyl -7-(but-2-ynyloxy)-2,3-dihydrobenzofuran,

a compound of formula (I) wherein n is 0, R₁ is CH₃, and R₂ is ann-hexyl substituent having Chemical Formula C₁₈H₂₄O₂ and MolecularWeight (MW) of 272.38 Dalton whose structure is confirmed by ¹H and ¹³CNMR analyses;

5-n-butyl-7-((prop-2-ynyloxy)methyl)-2,3-dihydrobenzofuran,

a compound of formula (I) wherein n is 1, R₁ is H, and R₂ is an n-butylsubstituent having Chemical Formula C₁₆H₂₀O₂ and Molecular Weight (MW)of 244.33 Dalton whose structure is confirmed by ¹H and ¹³C NMRanalyses;

5-n-hexyl-7-(prop-2-ynyloxy)-2,3-dihydrobenzofuran,

a compound of formula (I) wherein n is 0, R₁ is H, and R₂ is an n-butylsubstituent having Chemical Formula C₁₇H₂₂O₂ and Molecular Weight (MW)of 258.36 Dalton whose structure is confirmed by ¹H and ¹³C NMRanalyses;

5-n-propyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran,

a compound of formula (I) wherein n is 1, R₁ is CH₃, and R₂ is an-propyl substituent having Chemical Formula C₁₆H₂₀O₂ and MolecularWeight (MW) of 244.33 Dalton whose structure is confirmed by ¹H and ¹³CNMR analyses;

5-n-propyl-7-((prop-2-ynyloxy)methyl)-2,3-dihydrobenzofuran,

a compound of formula (I) wherein n is 1, R₁ is H, and R₂ is a n-propylsubstituent having Chemical Formula C₁₅H₁₈O₂ and Molecular Weight (MW)of 230.30 Dalton whose structure is confirmed by ¹H and ¹³C NMRanalyses.

The compound of the invention is more preferably one of:

-   5-n-hexyl-7-((prop-2-ynyloxy)methyl)-2,3-dihydrobenzofuran-   5-n-hexyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran-   5-n-butyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran-   5-n-butyl-7-((prop-2-ynyloxy)methyl)-2,3-dihydrobenzofuran-   5-n-propyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran

Still more preferably5-n-butyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran and5-n-propyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran

In a further aspect the invention concerns an insecticide compositioncomprising at least one insecticide active ingredient and at least onecompound of Formula (I)

-   wherein n is 0 or 1,-   R₁ is H or CH₃ and-   R₂ is a linear (C₃-C₆)alkyl.

The preferred compounds and the preferred meaning of n, R₁ and R₂ ofcompounds formula (I) used in the insecticide composition of theinvention are the same as stated above for compounds of Formula (I).

The compounds of the invention can be prepared by a process comprisingthe following steps:

-   a) Friedel Crafts acylation of 2.3-dihydrobenzofuran with the    suitable anhydride and in the presence of a Lewis catalyst.-   b) Hydrogenation of the ketone so obtained with hydrogen and in the    presence of catalyst chosen between Pd/c or Pt/C.-   c) Chloromethylation of the hydrogenated product coming from b) and    subsequent reaction with the suitable alcohol in the presence of    solid sodium hydroxide.

Specifically, following the above process the following compounds wereprepared:

-   5-n-hexyl-7-((prop-2-ynyloxy)methyl)-2,3-dihydrobenzofuran,-   5-n-hexyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran-   5-n-butyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran-   5-n-butyl 7-((prop-2-ynyloxy)methyl)-2,3-dihydrobenzofuran-   5-n-propyl 7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran and-   5-n-propyl 7-((prop-2-ynyloxy)methyl)-2,3-dihydrobenzofuran

Alternatively the compounds of the invention can be prepared by aprocess comprising the following steps:

-   d) Acylation(preferably acetylation) of the intermediates as in step    b);-   e) Baeyer Villiger oxidation of the compound coming from d) by    reaction with hydrogen peroxide to get the hydroxyl compound;-   f) Etherification of the compound coming from e) in the presence of    a base such as potassium carbonate and the suitable halogen alkynyl    compound.

Specifically, following the above process the following compounds wereprepared: 5-n-hexyl-7-(but-2-ynyloxy)-2,3-dihydrobenzofuran5-n-hexyl-7-(prop-2-ynyloxy)-2,3-dihydrobenzofuran

The position of the substituents on 2,3-dihydrobenzofuran ring wasconfirmed by NMR analyses, in particular by the technique of NuclearOverhauser Effect (NOE) and gradient-selected ¹H-¹H COSY (COrrelatedSpectroscopY)

The insecticide composition of the present invention comprises thepresent compounds of the formula (I) and an insecticide activeingredient.

The ratio between the present 2,3-dihydrobenzofuran compound of theformula (I) and the insecticide active ingredient which are contained inthe insecticide composition of the present invention is optionallyadjustable without limitation according to the control objectives suchas kinds of insects, application places, applying times, kinds of theinsecticide active ingredient. Typical weight ratio of the presentcompound to insecticide active ingredient is from about 1:100 to about100:1, preferably from about 1:50 to about 50:1, more preferably from20:1 to 1:1.

Examples of the insecticide active ingredient of the present insecticidecomposition are:

-   pyrethroid compounds such as allethrin, tetramethrin, prallethrin,    phenothrin, resmethrin, cyphenothrin, permethrin, cypermethrin,    alpha-cypermethrin, zeta-cypermethrin, deltamethrin, tralomethrin,    cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin,    flumethrin, imiprothrin, etofenprox, fenvalerate, esfenvalerate,    fenpropathrin, silafluofen, bifenthrin, transfluthrin,    flucythrinate, tau-fluvalinate, acrinathrin, tefluthrin,    cycloprothrin,    2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl-(EZ)-(1RS,3RS;1RS,3SR)-2,2-dimethyl-3-prop-1-enylcyclopropanecarboxylate,    2,3,5,6-tetrafluoro-4-methylbenzyl(EZ)-(1RS,3RS;1RS,3SR)-2,2-dimethyl-3-prop-1-enylcyclopropanecarboxylate,    2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl(1RS,3RS;1RS,3SR)-2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropanecarboxylate,    empenthrin,    2,3,5,6-tetrafluoro-4-methoxymethylbenzyl(EZ)-(1RS,3RS;1RS,3SR)-3-(2-cyan-o-1-propenyl)-2,2-dimethylcyclopropanecarboxylate,    2,3,5,6-tetrafluoro-4-methoxymethylbenzyl(EZ)-(1RS,3RS;1RS,3SR)-3-(2-cyan-o-2-ethoxycarbonylvinyl)-2,2-dimethylcyclopropanecarboxylate,    2,3,5,6-tetrafluoro-4-methoxymethylbenzyl(1RS,3RS;1RS,3SR)-3-(2,2-dichlor-ovinyl)-2,2-dimethylcyclopropanecarboxylate,    2,3,5,6-tetrafluoro-4-methoxymethylbenzyl(EZ)-(1RS,3RS;1    RS,3SR)-3-methoxy-iminomethyl-2,2-dimethylcyclopropanecarboxylate    and 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl(EZ)-(1RS,3RS;1    RS,3SR)-3-(2-etho-xycarbonyl-2-fluorovinyl)-2,2-dimethylcyclopropanecarboxylate;-   organic phosphorus compounds such as dichlorvos, fenitrothion,    cyanophos, profenofos, sulprofos, phenthoate, isoxathion,    tetrachlorvinphos, fenthion, chlorpyriphos, diazinon, acephate,    terbufos, phorate, chlorethoxyfos, fosthiazate, ethoprophos,    cadusafos and methidathion; carbamate compounds such as propoxur,    carbaryl, metoxadiazone, fenobucarb, methomyl, thiodicarb,    alanycarb, benfuracarb, oxamyl, aldicarb and methiocarb;    benzoylphenylurea compounds such as lufenuron, chlorfluazuron,    hexaflumuron, diflubenzuron, triflumuron, teflubenzuron,    flufenoxuron, fluazuron, novaluron, triazuron and bistrifluron;    juvenile hormone-like substances such as pyriproxyfen, methoprene,    hydroprene and fenoxycarb;-   neonicotinoid compounds such as acetamiprid, nitenpyram,    thiacloprid, thiamethoxam, dinotefuran, imidacloprid and    clothianidin;-   phenylpyrazole compounds such as acetoprole and ethiprole;

benzoylhydrazine compounds such as tebufenozide, chromafenozide,methoxyfenozide and halofenozide;

-   other insecticide active ingredients such as diafenthiuron,    pymetrozine, flonicamid, triazamate, buprofezin, spinosad, emamectin    benzoate, chlorfenapyr, indoxacarb MP, pyridalyl, cyromazine,    fenpyroximate, tebufenpyrad, tolfenpyrad, pyridaben, pyrimidifen,    fluacrypyrim, etoxazole, fenazaquin, acequinocyl, hexythiazox,    clofentezine, fenbutatin oxide, dicofol, propargite, abamectin,    milbemectin, amitraz, cartap, bensultap, thiocyclam, endosulfan,    spirodiclofen, spiromesifen, amidoflumet and azadirachtin.

The insecticide composition of the present invention can also comprise asolid carrier, a liquid carrier and/or a gaseous carrier and, further,if necessary, excipients selected from a surfactant and other adjuvantsto have an insecticide formulation.

The insecticide formulation can contain excipients to have an emulsion,an oil solution, a shampoo preparation, a flowable preparation, apowder, a wettable powder, a granule, a paste, a microcapsule, a foam,an aerosol, a carbon dioxide gas preparation, a tablet, a resinpreparation, a paper preparation, a nonwoven fabric preparation, and aknitted or woven fabric preparation. These preparations may be used inthe form of a poison bait, a insecticide coil, an electric insecticidemat, a smoking preparation, a fumigant or a sheet.

A preparation obtained with the insecticide composition of the presentinvention contains usually 0.01 to 98% by weight of the presentcomposition with respect to the total weight of the preparation.

A solid carrier used for the insecticide formulation includesfinely-divided powder or granules of clay (e.g., kaolin clay,diatomaceous earth, bentonite, Fubasami clay, acid clay, etc.),synthetic hydrated silicon oxide, talc, ceramics, other inorganicminerals (e.g., sericite, quartz, sulfur, activated carbon, calciumcarbonate, hydrated silica, calcium phosphate etc.), hydroxyapatite orchemical fertilizers (e.g., ammonium sulfate, ammonium phosphate,ammonium nitrate, ammonium chloride, urea, etc.); a substance which canbe sublimated and is in the solid form at normal temperature (e.g.,2,4,6-triisopropyl-1,3,5-trioxane, naphthalene, p-dichlorobenzene,camphor, adamantan, etc.); wool; silk; cotton; hemp; pulp; syntheticresins (e.g., polyethylene resins such as low-density polyethylene,straight low-density polyethylene and high-density polyethylene;ethylene-vinyl ester copolymers such as ethylene-vinyl acetatecopolymers; ethylene-methacrylic acid ester copolymers such asethylene-methyl methacrylate copolymers and ethylene-ethyl methacrylatecopolymers; ethylene-acrylic acid ester copolymers such asethylene-methyl acrylate copolymers and ethylene-ethyl acrylatecopolymers; ethylene-vinylcarboxylic acid copolymers such asethylene-acrylic acid copolymers; ethylene-tetracyclododecenecopolymers; polypropylene resins such as propylene homopolymers andpropylene-ethylene copolymers; poly-4-methylpentene-1, polybutene-1,polybutadiene, polystyrene; acrylonitrile-styrene resins; styreneelastomers such as acrylonitrile-butadiene-styrene resins,styrene-conjugated diene block copolymers, and styrene-conjugated dieneblock copolymer hydrides; fluororesins; acrylic resins such aspoly(methyl methacrylate); polyamide resins such as nylon 6 and nylon66; polyester resins such as polyethylene terephthalate, polyethylenenaphthalate, polybutylene terephthalate, andpolycyclohexylenedimethylene terephthalate; polycarbonates, polyacetals,polyacrylsulfones, polyarylates, hydroxybenzoic acid polyesters,polyetherimides, polyester carbonates, polyphenylene ether resins,polyvinyl chloride, polyvinylidene chloride, polyurethane, and porousresins such as foamed polyurethane, foamed polypropylene, or foamedethylene, etc.), glasses, metals, ceramics, fibers, cloths, knittedfabrics, sheets, papers, yarn, foam, porous substances, andmultifilaments.

A liquid carrier includes, for example, aromatic or aliphatichydrocarbons (e.g., xylene, toluene, alkylnaphthalene,phenylxylylethane, kerosene, gas oil, hexane, cyclohexane, etc.),halogenated hydrocarbons (e.g., chlorobenzene, dichloromethane,dichloroethane, trichloroethane, etc.), alcohols (e.g., methanol,ethanol, isopropyl alcohol, butanol, hexanol, benzyl alcohol, ethyleneglycol, etc.), ethers (e.g., diethyl ether, ethylene glycol dimethylether, diethylene glycol monomethyl ether, diethylene glycol monoethylether, propylene glycol monomethyl ether, tetrahydrofuran, dioxane,etc.), esters (e.g., ethyl acetate, butyl acetate, etc.), ketones (e.g.,acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone,etc.), nitriles (e.g., acetonitrile, isobutyronitrile, etc.), sulfoxides(e.g., dimethyl sulfoxide, etc.), amides (e.g., N,N-dimethylformamide,N,N-dimethylacetamide, cyclic imides (e.g. N-methylpyrrolidone)alkylidene carbonates (e.g., propylene carbonate, etc.), vegetable oil(e.g., soybean oil, cottonseed oil, etc.), vegetable essential oils(e.g., orange oil, hyssop oil, lemon oil, etc.), and water.

A gaseous carrier includes, for example, butane gas, flon gas, liquefiedpetroleum gas (LPG), dimethyl ether, and carbon dioxide gas.

A surfactant includes, for example, alkyl sulfate ester salts, alkylsulfonates, alkyl aryl sulfonates, alkyl aryl ethers andpolyoxyethylenated products thereof, polyethylene glycol ethers,polyvalent alcohol esters and sugar alcohol derivatives.

Other adjuvants for formulation include binders, dispersants andstabilizers, specifically, for example, casein, gelatin, polysaccharides(e.g., starch, gum arabic, cellulose derivatives, alginic acid, etc.),lignin derivatives, bentonite, sugars, synthetic water-soluble polymers(e.g., polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid, etc.),PAP (acidic isopropyl phosphate), BHT (2,6-di-t-butyl-4-methylphenol),BHA (a mixture of 2-t-butyl-4-methoxyphenol and3-t-butyl-4-methoxyphenol), vegetable oils, mineral oils, fatty acidsand fatty acid esters.

According to the invention the insecticide composition contain at leastone 2,3-dihydrobenzofuran derivative compound as synergistic compound.Other synergists can be present in the composition, also those known inthe art such as piperonyl butoxide, MGK 264 and Verbutin

The present compound can be used in insect control by applying aneffective amount of the present compound and a insecticide activeingredient, i.e. the present insecticide composition to insects directlyand/or a biotope thereof (e.g., plants, animals, soil, etc.).

Therefore, in yet a further aspect of the invention, the inventionrelates to the insecticide composition of the invention for use inveterinary medicine and in yet a further aspect of the invention, theinvention relates to the insecticide composition for use in treatingpediculosis in humans.

When the insecticide composition of the present invention is used forcontrolling insects in agriculture and forestry, the application amountis usually 1 to 5,000 g/ha, preferably 10 to 800 g/ha of total amount ofthe present active ingredient.

When the insecticide composition of the present invention is the form ofan emulsion, a wettable powder, a flowable agent, or a microcapsule, itis usually used after dilution with water so as to have the presentactive ingredient concentration of 0.01 to 1,000 ppm. When theinsecticide composition of the present invention is the form of an oilsolution, a powder or a granule, it is usually used as it is.

These preparations as it is may be sprayed as they are to plants to beprotected from insects, or may be diluted with water and then sprayed toa plant to be protected from insects. Soil can be treated with thesepreparations to control insects living in the soil. Seedbeds beforeplanting or planting holes or plant feet in planting can be also treatedwith these preparations. Further, a sheet preparation of the insecticidecomposition of the present invention may be applied by winding aroundplants, disposing in the vicinity of plants, laying on the soil surfaceat the plant feet or the like.

When the insecticide composition of the present invention is used for acontrol of insects of epidemic, the application amount is usually 0.001to 100 mg/m³ of total amount of the present active ingredient forapplication to space, and 0.001 to 1,000 mg/m² of total amount of thepresent active ingredient for application to a plane. When theinsecticide composition of the present invention is the form of anemulsion, a wettable powder or a flowable agent, it is usually appliedafter dilution with water so as to have the present active ingredientconcentration of 0.001 to 10,000 ppm, preferably 0.01 to 1,000 ppm. Whenthe insecticide composition of the present invention is the form of anoil solution, an aerosol, a smoking preparation or a poison bait, it isusually applied as it is. The insecticide composition in the form ofinsecticide coil, or an electric insecticide mat is applied by emittingthe present active ingredient by heating depending on its form. Theinsecticide composition in the form of a resin preparation, a paperpreparation, a tablet, a nonwoven fabric preparation, a knitted or wovenfabric preparation or a sheet preparation can be applied, for example,by leaving the preparation as it is in a space to be applied and bysending air to the preparation.

A space to which the insecticide composition of the present invention isapplied for prevention of epidemics includes, for example, a closet, aJapanese-style closet, a Japanese-style chest, a cupboard, a lavatory, abathroom, a lumber room, a living room, a dining room, a warehouse, andthe car inside. The insecticide composition may be also applied inoutdoor open space.

When the insecticide composition of the present invention is used forcontrolling parasites living outside of a livestock such as a cow, ahorse, a pig, a sheep, a goat or a chicken, or a small animal such as adog, a cat, a rat or a mouse, it can be used for said animal by a knownmethod in the veterinary filed. Specifically, when systemic control isintended, the insecticide composition is administered, for example, as atablet, a mixture with feed, a suppository or an injection (e.g.,intramuscularly, subcutaneously, intravenously, intraperitoneally,etc.). When non-systemic control is intended, a method of using theinsecticide composition of the present invention includes spraying,pour-on treatment or a spot-on treatment with the insecticidecomposition in the form of an oil solution or an aqueous liquid, washingan animal with the insecticide composition in the form of a shampoopreparation, and attachment of a collar or a ear tag made of theinsecticide composition in the form of a resin preparation to an animal.When administered to an animal, total amount of the present activeingredient is usually in the range of 0.01 to 300 mg per 1 kg bodyweight of the animal.

Insects against which the insecticide composition of the presentinvention has controlling effect include harmful arthropods such asinsects and mites. More specifically, examples thereof are listed below.

Hemiptera; Delphacidae such as Laodelphax striatellus, Nilaparvatalugens, Sogatella furcifera and the like; Deltocephalidae such asNephotettix cincticeps, Nephotettix virescens and the like; Aphididaesuch as Aphis gossypii, Myzus persicae and the like, Pentatomidae andAlydidae, such as Nezara antennata, Riptortus clavetus, Eysarcorislewisi, Eysarcoris parvus, Plautia stali, Halyomorpha mista and thelike, Aleyrodidae such as Trialeurodes vaporariorum, Bemisiaargentifolii and the like, Diaspididae, Coccidae and Margarodidae, suchas Aonidiella aurantii, Comstockaspis perniciosa, Unaspis citri,Ceroplastes rubens, Icerya purchasi and the like, Tingidae, Cimicidaesuch as Cimex lectularius and the like, Psyllidae, and the like;Lepidoptera; Pyralidae such as Chilo suppressalis, Cnaphalocrocismedinalis, Notarcha derogata, Plodia interpunctella and the like,Noctuidae such as Spodoptera litura, Pseudaletia separata, Trichoplusiaspp., Heliothis spp., Helicoverpa spp. and the like, Pieridae such asPieris rapae and the like, Tortricidae such as Adoxophyes spp.,Grapholita molesta, Cydia pomonella and the like, Carposinidae such asCarposina niponensis and the like, Lyonetiidae such as Lyonetia spp. andthe like, Lymantriidae such as Lymantria spp., Euproctis spp. and thelike, Yponomeutidae such as Plutella xylostella and the like,Gelechiidae such as Pectinophora gossypiella and the like, Arctiidaesuch as Hyphantria cunea and the like, Tineidae such as Tineatranslucens, Tineola bisselliella and the like; Diptera: Culicidae suchas Culex pipiens pallens, Culex tritaeniorhynchus, Culexquinquefasciatus and the like, Aedes spp. such as Aedes aegypti, Aedesalbopictus and the like, Anopheles spp. such as Anopheles sinensis andthe like, Chironomidae, Muscidae such as Musca domestica, Muscinastabulans and the like, Calliphoridae, Sarcophagidae, Fanniidae,Anthomyiidae such as Delia latura, Delia antiqua and the like,

Tephritidae, Drosophilidae, Phoridae such as Megaselia spiracularis andthe like, sychodidae such as Clogmia albipunctata and the like,

Simuliidae, Tabanidae, Stomoxys spp., Agromyzidae, and the like;Coleoptera: rn rootworms such as Diabrotica virgifera virgifera,Diabrotica undecimpunctata howardi and the like,

Scarabaeidae such as Anomala cuprea, Anomala rufocuprea and the like,

Rhynchophoridae, Curculionidae and Bruchidae, such as Sitophiluszeamais, Lissorhoptrus oryzophilus, Callosobruchus chienensis and thelike, Tenebrionidae such as Tenebrio molitor, Tribolium castaneum andthe like, Chrysomelidae such as Oulema oryzae, Aulacophora femoralis,Phyllotreta striolata, Leptinotarsa decemlineata and the like,Dermestidae such as Dermestes maculates and the like, Anobiidae,Epilachna spp. such as Epilachna vigintioctopunctata and the like,Lyctidae, Bostrychidae, Ptinidae, Cerambycidae, Paederus fuscipes, andthe like; Blattaria: Blattella germanica, Periplaneta fuliginosa,Periplaneta americana, Periplaneta brunnea, Blatta orientalis and thelike; Thysanoptera: Thrips palmi, Thrips tabaci, Frankliniellaoccidentalis, Frankliniella intonsa and the like; Hymenoptera:Formicidae such as Monomorium pharaosis, Formica fusca japonica,Ochetellus glaber, Pristomyrmex pungens, Pheidole noda, and the like;Vespidae, Bethylidae, Tenthredinidae such as Athalia japonica, and thelike; Orthoptera: Gryllotalpidae, Acrididae, and the like; Aphaniptera:Ctenocephalides felis, Ctenocephalides canis, Pulex irritans, Xenopsyllacheopis, and the like; Anoplura: Pediculus humanus corporis, Phthiruspubis, Haematopinus eurysternus, Dalmalinia ovis, and the like;Isoptera: Subterranean termites such as Reticulitermes speratus,Coptotermes formosanus, Reticulitermes flavipes, Reticulitermeshesperus, Reticulitermes virginicus, Reticulitermes tibialis,Heterotermes aureus, and the like, Dry wood termites such asIncisitermes minor, and the like, Damp wood termites such asZootermopsis nevadensis, and the like; Acarina: Tetranychidae such asTetranychus urticae, Tetranychus kanzawai, Panonychus citri, Panonychusulmi, Oligonychus spp. and the like, Eriophyidae such as Aculopspelekassi, Aculus schlechtendali, and the like, Tarsonemidae such asPolyphagotarsonemus latus, and the like, Tenuipalpidae, Tuckerellidae,Ixodidae such as Haemaphysalis longicornis, Haemaphysalis flava,Dermacentor variabilis, Ixodes ovatus, Ixodes persulcatus, Ixodesscapularis, Boophilus microplus, Amblyomma americanum, Rhipicephalussanguineus, and the like,

Acaridae such as Tyrophagus putrescentiae, and the like, Epidermoptidaesuch as Dermatophagoides farinae, Dermatophagoides ptrenyssnus, and thelike, Cheyletidae such as Cheyletus eruditus, Cheyletus malaccensis,Cheyletus moorei, Ornithoonyssus bacoti, Ornithonyssus sylvairum and thelike, Dermanyssidae such as Dermanyssus gallinae, and the like,Trombiculidae such as Leptotrombidium akamushi, and the like; Araneae:Chiracanthium japonicum, Latrodectus hasseltii, and the like; Chilopoda:Thereuonema hilgendorfi, Scolopendra subspinipes, and the like;Diplopoda: Oxidus gracilis, Nedyopus tambanus, and the like; Isopoda:Armadillidium vulgare, and the like; Gastropoda: Limax marginatus, Limaxflavus, and the like.

The insecticide composition of the present invention is preferablysuitable for agriculture for professional insect control operators andfor household application.

In particular the insecticide composition of the present invention issuitable for the following insect orders: Hemiptera, Diptera, Blattaria,Thysanoptera, Isoptera, and Acarina

The invention will be now detailed by means of the following examplesrelating to the preparation of some invention synergistic compounds andto the evaluation of their activity

EXPERIMENTAL PART

Preparation of the Compounds of Formula (I)

Example 1 Synthesis of5-n-hexyl-7-((prop-2-ynyloxy)methyl)-2,3-dihydrobenzofuran a) Synthesisof 5-n-hexyl-2,3-dihydrobenzofuran

The compound was prepared following the procedure reported in U.S. Pat.No. 6,342,613 starting from 109.3 g (0.5 mol) of hexanoic anhydride(purity 98%), 120.1 g (1.0 mol) of 2,3-dihydrobenzofuran and 6.8 g (0.05mol) of zinc chloride. The reaction was carried out at 100° C. for 4hrs, cooled down to room temperature, washed with acidic water and theorganic phase separated off. The organic phase was washed twice withwater, dried on anhydrous sodium sulphate, filtered, distilled u.v (55°C./150 Pa) and subsequently at 133° C./30 Pa, obtaining 107.2 g of ayellow oil product, that was hydrogenated on Pd/C at 140° C./0.6 MPa for7 hrs. After filtration of the catalyst, 92.9 g of an oil product wasobtained whose NMR (¹H and ¹³C) and GC-MS analyses conformed to thestructure

¹H NMR (400 MHz, CDCl₃) d=0.86-0.90 (m, 3H, CH₃), 1.27-1.35 (m, 6H,3CH₂), 1.52-1.60 (m, 2H, CH₂), 2.51 (t, J=7.81 Hz, 2H, CH₂), 3.15 (t,J=8.69 Hz, 2H, CH₂), 4.51 (t, J=8.69 Hz, 2H, CH₂), 6.68 (d, Jo=8.20 Hz,1H, Ar—CH), 6.89 (d, Jo=8.20 Hz, 1H, Ar—CH), 6.99 (s br, 1H, Ar—CH).

¹³C NMR (100 MHz, CDCl₃): d=14.06 (CH₃), 22.60 (CH₂), 28.94 (CH₂), 29.80(CH₂), 31.73 (CH₂), 31.99 (CH₂), 35.36 (CH₂), 71.00 (CH₂), 108.75(Ar—CH), 124.76 (Ar—CH), 126.72 (Ar—C), 127.62 (Ar—CH), 134.90 (Ar—C),158.01 (Ar—C).

GC-MS (El) m/z (%): 204 (60) [M+], 146 (3), 133 (100), 149 (100), 115(4), 91 (6), 77 (10).

b) Synthesis of5-n-hexyl-7-((prop-2-ynyloxy)methyl)-2,3-dihydrobenzofuran

In a flask equipped with a stirrer 92.4 g (0.45 mol) of5-hexyl-2,3-dihydrobenzofuran were added with 19.3 g (0.63 mol) ofparaformaldehyde (purity 96.2%), 2.5 g (0.018 mol) of zinc chloride and183 g (1.86 mol) of HCl 37%.The mixture was the heated to 70° C. andmaintained under stirring for further 35 hrs. The solution was thencooled down to 30° C., added with 100 ml of toluene and the organicphase was separated off. The organic phase was then added slowly to amixture prepared by reacting 17.4 g (0.31 mol) of propargyl alcohol and15.6 g (0.39 mol) of solid sodium hydroxide at 60° C. for half an hour.After the addition the mixture is maintained under stirring at 60° C.for 4 hrs, cooled down to room temperature and added with 60 ml of NaCl10% aqueous solution under stirring. The organic solution is thenseparated off and the solvent evaporated u.v (25° C./50 Pa). The oilresidue was then distilled at 145° -150° C./50 Pa, thus obtaining 18.4 gof an oil product whose NMR (¹H and ¹³C) and GC/MS analyses conformed tothe structure

¹H NMR (400 MHz, CDCl₃): δ=0.88 (m, 3H, CH₃), 1.27-1.34 (m, 6H, 3CH₂),1.56 (m, 2H, CH₂), 2.45 (t, J=2.34 Hz, 1H, CH), 2.52 (t, J=7.81 Hz, 2H,CH₂), 3.17 (t, J=8.59 Hz, 2H, CH₂), 4.19 (d, J=2.34 Hz, 2H, CH₂), 4.56(t, J=8.59 Hz, 2H, CH₂), 4.57 (s, 2H, CH₂), 6.94 (s, 1H, Ar—CH), 6.96(s, 1H, Ar—CH).

¹³C NMR (100 MHz, CDCl₃): δ=14.10 (CH₃), 22.62 (CH₂), 28.99 (CH₂), 29.85(CH₂), 31.75 (CH₂), 31.98 (CH₂), 35.37 (CH₂), 57.24 (CH₂), 66.62 (CH₂),71.33 (CH₂), 74.42 (C), 79.90 (C), 118.25 (Ar—C), 124.65 (Ar—CH), 126.96(Ar—C), 128.19 (Ar—CH), 135.08 (Ar—C), 156.42 (Ar—C).

GC-MS (El) m/z (%): 272 (79) [M+], 217 (24), 201 (100), 161 (23), 147(42), 133 (12), 115 (10), 91 (10).

Example 2 Synthesis of5-n-hexyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran

Following the same procedure described in Example 1b), but starting from79.6 g (0.39 mol) of 5-hexyl-2,3-dihydrobenzofuran, 19.3 g (0.63 mol) ofparaformaldehyde (purity 96.2%), 2.5 g (0.018 mol) of zinc chloride and183 g (1.86 mol) of HCl 37%, 21.7 g (0.31 mol) of 2-butyn-1-ol and 15.5g (0.39 mol) of solid sodium hydroxide, 26.1 g of an oil product wasobtained after distillation at 158-168° C./70Pa whose NMR (¹H and ¹³C)and GC/MS analyses conformed to the structure.

¹H NMR (400 MHz, CDCl₃): δ=0.88 (m, 3H, CH₃), 1.27-1.34 (m, 6H, 3CH₂),1.56 (m, 2H, CH₂), 1.87 (t, J=2.34 Hz, 3H, CH₃), 2.52 (m, 2H, CH₂), 3.16(t, J=8.59 Hz, 2H, CH₂), 4.15 (q, J=2.34 Hz, 2H, CH₂), 4.54 (s, 2H,CH₂), 4.55, (t, J=8.59 Hz, 2H, CH₂), 6.95 (s, 2H, 2Ar—CH).

¹³C NMR (100 MHz, CDCl₃): δ=3.66 (CH₃), 14.09 (CH₃), 22.61 (CH₂), 29.00(CH₂), 29.85 (CH₂), 31.75 (CH₂), 31.99 (CH₂), 35.38 (CH₂), 57.91 (CH₂),66.49 (CH₂), 71.27 (CH₂), 75.28 (C), 82.42 (C), 118.65 (Ar—C), 124.43(Ar—CH), 126.84 (Ar—C), 128.04 (Ar—CH), 135.01 (Ar—C)), 156.29 (Ar—C).

GC-MS (El) m/z (%): 286 (100) [M+], 231 (35), 217 (71), 201 (14), 185(22), 161 (28), 147 (80), 133 (31), 115 (11), 91 (14).

Example 3 Synthesis of5-n-butyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran a) Synthesisof 5-n-butyl-2,3-dihydrobenzofuran

Following the same procedure described in Example 1a), but starting from120.1 g (1.0 mol) of 2,3-dihydrobenzofuran, 92.0 g (0.54 mol) of butyricanhydride and 7.63 g (0.056 mol) of zinc chloride 116.8 g of an oilproduct was obtained after distillation at 122-128° C./50 Pa. Thecompound was then hydrogenated on Pd/C at 140° C./0.6 MPa for 7 hrs.After filtration of the catalyst, 92.5 g of an oil product was obtainedwhose NMR (¹H and ¹³C) and GC-MS analyses conformed to the structure

1H NMR (400 MHz, CDCl₃): d=0.99 (t, J=7.42 Hz, 3H, CH3), 1.37-1.46 (tq,J1=7.81 Hz, J2=7.42 Hz, 2H, CH2), 1.60-1.66 (m, 2H, CH2), 2.60 (t,J=7.71 Hz, 2H, CH₂), 3.22 (t, J=8.65 Hz, 2H, CH₂), 4.58 (t, J=8.65 Hz,2H, CH₂), 6.75 (d, Jo=8.10 Hz, 1H, Ar—CH), 6.96 (d, Jo=8.10 Hz, 1H,Ar—CH), 7.02 (s br 1H, Ar—CH).

¹³C NMR (100 MHz, CDCl₃): d=13.91 (CH₃), 22.26 (CH₂), 29.77 (CH₂), 34.16(CH₂), 35.01 (CH₂), 70.98 (CH₂), 108.72 (Ar—CH), 124.76 (Ar—CH), 127.71(Ar—C), 127.62 (Ar—CH), 134.82 (Ar—C), 158.00 (Ar—C).

GC-MS (El) m/z (%): 176 (22) [M+], 133 (100)

b) Synthesis of5-n-butyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran

Following the same procedure of Example 2, but starting from 55.0 g(0.31 mol) of 5-n-butyl-2,3-dihydrobenzofuran, 15.0 g (0.50 mol) ofparaformaldehyde (purity 96.2%) and 140 g (1.42 mol) of HCl 37%, 18.9 g(0.27 mol) of 2-butyn-1-ol and 11.8 g (0.295 mol) of solid sodiumhydroxide, 34.5 g of an oil product was obtained after distillation at134°-138° C./20 Pa, whose NMR (¹H and ¹³C) and GC/MS analyses conformedto the structure

¹H NMR (400 MHz, CDCl₃): δ=0.92 (t, J=7.42 Hz, 3H, CH₃), 1.34 (tq,J₁=7.81 Hz, J₂=7.42 Hz, 2H, CH₂), 1.55 (m, 2H, CH₂), 1.86 (t, J=2.34 Hz,3H, CH₃), 2.52 (t, J=7.81 Hz, 2H, CH₂), 3.16 (t, J=8.59 Hz, 2H, CH₂),4.15 (q, J=2.34 Hz, 2H, CH₂), 4.54 (s, 2H, CH₂), 4.55 (t, J=8.59 Hz, 2H,CH₂), 6.95 (s, 2H, Ar—CH).

¹³C NMR (100 MHz, CDCl₃): δ=3.60 (CH₃), 13.91 (CH₃), 22,29 (CH₂), 29.80(CH₂), 34.12 (CH₂), 34.99 (CH₂), 57.87 (CH₂), 66.43 (CH₂), 71,21 (CH₂),75.23 (C), 82.36 (C), 118.60 (Ar—C), 124.39 (Ar—CH), 126.78 (Ar—C),127.99 (Ar—CH), 134.89 (Ar—C), 156.23 (Ar—C).

GC-MS (El) m/z (%): 258 (100) [M+], 215 (44), 189 (85), 161 (37), 147(92), 133 (38).

Example 4 Synthesis of 5-n-hexyl-7-(but-2-ynyloxy)-2,3-dihydrobenzofurana) Synthesis of 5-n-hexyl-7-acetyl-2,3-dihydrobenzofuran

A mixture of 455.1 g (2.23 mol) of the compound of Example 1a), (143.0g) 1.40 mol) of acetic anhydride and 19.1 g (0.14 mol) of zinc chloridewas heated to 100° C. under stirring for 7 hrs. The mixture was thenadded with further 143.0 g (1.4 mol) of acetic anhydride and 19.1 g(0.14 mol) of zinc chloride. The mixture was stirred at 100° C. forfurther 5 hrs, cooled down to room temperature and added with 200 ml ofdiisopropyl ether and 200 ml of an aqueous solution of HCl (1.4 M). Theorganic phase was separated off, washed with water and dried onanhydrous sodium sulphate. After filtration, the organic phase wasdistilled u.v. at 30° C./180Pa and at 143°-145° C./30 Pa, thus obtaining310 g of a thick oil, whose NMR (¹H and ¹³C) and GC-MS analysesconformed to the structure.

¹H NMR (400 MHz, CDCl₃): δ=0.86-0.89 (m, 3H, CH₃), 1.27-1.33 (m, 6H,3CH₂), 1.53-1.60 (m, 2H, CH₂), 2.54 (t, J=7.76 Hz; 2H, CH₂), 2.60 (s,3H, CH₃), 3.20 (t, J=8.73 Hz; 2H, CH₂), 4.66 (t, J=8.73 Hz; 2H, CH₂),7.17 (s br, 1H, Ar—CH), 7.48 (s br, 1H, Ar—CH).

¹³C NMR (100 MHz, CDCl₃): δ=14.01 (CH₃), 22.52 (CH₂),28.83 (CH₂), 29.02(CH₂), 30.86 (CH₃), 31.63 (CH₂), 31.66 (CH₂), 35.06(CH₂), 71.86 (CH₂),120.12 (Ar—C), 127.20 (Ar—CH), 129.13 (Ar—C), 129.84 (Ar—CH), 134.94(Ar—C), 158.62 (Ar—C), 197.17 (C═O).

GC-MS (El) m/z (%): 246 (30) [M+], 231 (20), 175 (100), 157 (12)

b) Synthesis of 5-n-hexyl-7-hydroxy-2,3-dihydrobenzofuran

A mixture of 104.3 g (0.42 mol) of5-n-hexyl-7-acetyl-2,3-dihydrobenzofuran,80 g (1.715 mo) of formic acidand 200 ml of dichloromethane was heated to 40° C. under stirring. 125.0g (1.287 mol) of an aqueous solution of hydrogen peroxide 35% was thenadded slowly, maintaining an addition speed of 0.6 ml/min.

The solution was then stirred at 40° C. for further 3 hrs and then addedagain with 50 g (0.51 mol) of an aqueous solution of hydrogen peroxide35%.

The mixture was maintained at 40° C. under stirring for further 7 hrs,cooled to room temperature and the organic phase was separated andevaporated u.v (20° C./500Pa). 140.2 g of an oil compound was obtainedthat was mixed with 166 ml of sodium hydroxide aqueous solution (3M), 15ml of methanol and 50 ml of water. The mixture was heated to 45° C. for4 hrs, cooled to 20° C. and the solid product filtered and aftercrystallization from diisopropyl ether, obtaining 76.3 g of a whitesolid whose NMR (¹H and ¹³C) and GC-MS analyses conformed to thestructure.

¹H NMR (400 MHz, CDCl₃): d=0.88-0.91 (m, 3H, CH₃), 1.28-1.34 (m, 6H,3CH₂), 1.53-1.60 (m, 2H, CH₂), 2.50 (t, J=7.81 Hz, 2H, CH₂), 3,21 (t,J=8.59 Hz, 2H, CH₂), 4.60 (t, J=8.59 Hz, 2H, CH₂), 5.26 (s br, 1H, OH),6.58 (s, 1H, Ar—CH), 6.60 (s, 1H, Ar—CH).

¹³C NMR (100 MHz, CDCl₃): d=14.07 (CH₃), 22.59 (CH₂), 28.92 (CH₂), 30.52(CH₂), 31.72 (CH₂), 31.84 (CH₂), 35.49 (CH₂), 71.93 (CH₂), 114.85(Ar—CH), 116.52 (Ar—CH), 127.60 (Ar—C), 136.64 (Ar—C), 139.75 (Ar—C),144.51 (Ar—C).

GC-MS (El) m/z (%): 220 (66) [M+], 203 (1), 149 (100), 136 (2), 91(8),77 (10).

c) Synthesis of 5-n-hexyl-7-(but-2-ynyloxy)-2,3-dihydrobenzofuran

A mixture of 20.1 g (0.091 mol) of5-n-hexyl-7-hydroxy-2,3-dihydrobenzofuran, 12.8 g (0.091 mol) ofanhydrous potassium carbonate, 100 ml of acetone and 11.31 g (0.085 mol)of 1-bromo-2-butyne was heated to reflux for 10 hrs. The mixture was thecooled down to room temperature, filtered and the organic solutionevaporated u.v (25° C./500 Pa). 25.3 g of an oil product was obtainedwhose NMR (¹H and ¹³C) and GC/MS analyses conformed to the structure.

¹H NMR (400 MHz, CDCl₃): δ=0.88-0.91 (m, 3H, CH₃), 1,28-1.35 (m, 6H,3CH₂), 1.54-1.62 (m, 2H, CH₂), 1.83 (t, J=2.34 Hz, 3H, CH₃), 2.53 (m,2H, CH₂), 3.16 (t, J=8.59 Hz, 2H, CH₂), 4.56 (t, J=8.59 Hz, 2H, CH₂),4.69 (q, J=2.34 Hz, 2H, CH₂), 6.67 (s, 2H, Ar—CH).

¹³C NMR (100 MHz, CDCl₃): δ=3.42 (CH₃), 13.89 (CH₃), 22.42 (CH₂), 28.70(CH₂), 30.09 (CH₂), 31.58 (CH₂), 31.73 (CH₂), 35.47 (CH₂), 57.16 (CH₂),71.44 (CH₂), 74.17 (C), 83.33), 113.86 (Ar—CH), 117.52 (Ar—CH), 128.05(Ar—C), 135.56 (Ar—C), 141.79 (Ar—C), 146.56 (Ar—C).

GC-MS (El) m/z (%): 272 (100) [M+], 219 (30), 201 (60), 187 (20), 149(100), 121 (9), 91 (19).

Example 5 Synthesis of5-n-butyl-7-((prop-2-ynyloxy)methyl)-2,3-dihydrobenzofuran

Following the procedure of Example 3b), but starting from 50.7 g (0.288mol) of 5-n-butyl-2,3-dihydrobenzofuran, 15.0 g (0.5 mol) ofparaformaldehyde, 140 g (1.42 mol) of HCl 37%, 14.9.0 g (0.265 mol) ofpropargyl alcohol and 11.8 g (0.295 mol) of solid sodium hydroxide, 24.5g of an oil product is obtained after distillation at 124°-131° C./15 Pawhose NMR (¹H and ¹³C) and GC/MS analyses conformed to the structure

¹H NMR (400 MHz, CDCl₃): δ=0.93 (t, J=7.42 Hz, 3H, CH₃), 1.36 (tq,J₁=7.81 Hz, J₂=7.42 Hz, 2H, CH₂), 1.57 (m, 2H, CH₂), 2.47 (t, J=2.34 Hz,1H, CH₃), 2.54 (t, J=7.81 Hz, 2H, CH₂), 3.18 (t, J=8.59 Hz, 2H, CH₂),4.21 (d, J=2.34 Hz, 2H, CH₂), 4.57 (t, J=8.59 Hz, 2H, CH₂), 4.58 (s, 2H,CH₂), 6.96 (s, 1H, Ar—CH), 6.97 (s, 1H, Ar—CH).

¹³C NMR (100 MHz, CDCl₃): δ=13.88 (CH₃), 22.24 (CH₂), 29.75 (CH₂), 34.07(CH₂), 34.94 (CH₂), 57.14 (CH₂), 66.50 (CH₂), 71.21 (CH₂), 74.36 (CH),79.79 (C), 118.16 (Ar—C), 124.55 (Ar—CH), 126.85 (Ar—C), 128.07 (Ar—CH),134.89 (Ar—C), 156.30 (Ar—C).

GC-MS (EN 16-43/1) (El) m/z (%): 244 (69) [M+], 201 (100), 189 (31), 161(27), 147 (44), 133 (13), 151 (12), 91 (12).

Example 6 Synthesis of5-n-hexyl-7-(prop-2-ynyloxy)-2,3-dihydrobenzofuran

Following the procedure of Example 4c), a mixture of 20.1 g (0.091 mol)of 5-n-hexyl-7-hydroxy-2,3-dihydrobenzofuran, 12.8 g (0.093 mol) ofanhydrous potassium carbonate, 100 ml of acetone and 11.1 g (0.093 mol)of propargyl bromide was heated to reflux for 10 hrs. The mixture wasthe cooled down to room temperature, filtered and the organic solutionevaporated u.v (25° C./500 Pa). 24.2 g of an oil product was obtainedwhose NMR (¹H and ¹³C) and GC/MS analyses conformed to the structure.

¹H NMR (400 MHz, CDCl₃): δ=0.86-0.90 (m, 3H, CH₃), 1.27-1.34 (m, 6H,3CH₂), 1.57 (m, 2H, CH₂), 2.47 (t, J=2.54 Hz, 1H, CH), 2.52 (m, 2H,CH₂), 3.16 (t, J=8.59 Hz, 2H, CH₂), 4.57 (t, J=8.59 Hz, 2H, CH₂), 4.74(d, J=2.54 Hz, 2H, CH₂), 6.67 (s, 1H, Ar—CH), 6.68 (s, 1H, Ar—CH).

¹³C NMR (100 MHz, CDCl₃): δ=14.00 (CH₃), 22.53 (CH₂), 28.81 (CH₂), 30.17(CH₂), 31.65 (CH₂), 31.77 (CH₂), 35.53 (CH₂), 56.79 (CH₂), 71.64 (CH₂),75.32 (CH), 78.78 (C), 114.43 (Ar—CH), 118.11 (Ar—CH), 128.41 (Ar—C),135.77 (Ar—C), 141.51 (Ar—C), 146.74 (Ar—C).

GC-MS (El) m/z(%): 258 (100) [M+], 219 (48), 187 (37), 173 (18), 159(17), 149 (100), 91 (27), 77 (10).

Example 7 Synthesis of5-n-propyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran a) Synthesisof 5-n-propyl-2,3-dihydrobenzofuran

Following the procedure of Example 1a), a mixture of 58.7 g (0.45 mol)of propionic anhydride, 100.0 g (0.83 mol) of 2,3-dihydrobenzofuran and6.2 g (0.045 mol) of zinc chloride was heated at 100° C. for 2 hrs understirring, cooled down to room temperature, washed with acidic water andthe organic phase separated off. The organic phase was washed twice withwater, dried on anhydrous sodium sulphate, filtered, distilled u.v (30°C./150 Pa) and then at 109°-112° C./40 Pa, obtaining 66.8 g of acolorless oil product, that was hydrogenated on Pd/C at 140° C./0.6MPafor 7 hrs. After filtration of the catalyst, 63.2 g of an oil product isobtained whose NMR (¹H and ¹³C) and GC-MS analyses conformed to thestructure.

¹H NMR (400 MHz, CDCl₃)): δ=0.88-0.93 (m, 3H, CH₃), 1.51-1.57 (m, 2H,CH₂), 2.49 (t, J=8 Hz, 2H, CH₂), 3.14 (t, J=8 Hz, 2H, CH₂), 4.51 (m, 2H,CH₂), 6.92 (s 1H, Ar—CH), 6.95 (s 1H, Ar—CH).

¹³C NMR (100 MHz, CDCl₃) δ=13.59 (CH₃), 19.06 (CH₂), 24.79 (CH₂), 119.01(Ar—C), 124.03 (Ar—CH), 126.47 (Ar—C), 127.67 (Ar—CH), 134.43 (Ar—C),155.96 (Ar—C).

GC-MS (El) m/z (%): 162 (50) [M+], 133 (100), 91 (5), 77 (10)

b) Synthesis of5-n-propyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran

Following the procedure of Example 1b) 45.3 g (0.28 mol) of5-n-propyl-2,3-dihydrobenzofuran were added with 15.0 g (0.50 mol) ofparaformaldehyde (purity 96.2%) and 140 g (1.42 mol) of HCl 37%.Themixture was then heated to 60° C. and maintained under stirring forfurther 6 hrs. The solution was then cooled down to 30° C., added with50 ml of diisopropyl ether and the organic phase was separated off. Theorganic phase was then added slowly to a mixture prepared by reacting17.6 g (0.25 mol) of 2-butyn-1-ol and 11.3 g (0.28 mol) of solid sodiumhydroxide at 60° C. for half an hour. After the addition the mixture ismaintained under stirring at 60° C. for 10 hrs, cooled down to roomtemperature and added with 60 ml of NaCl 10% aqueous solution understirring. The organic solution is then separated off and the solventevaporated u.v (25° C./500 Pa). The oil residue was then distilled at131°-134° C./10 Pa obtaining 29.7 g of an oil product whose NMR (¹H and¹³C) and GC/MS analyses conform to the structure

¹H NMR (400 MHz, CDCl₃) (EN 16-46/2): δ=0.92 (t, 3H, J=7.42 Hz,CH₃(12)), 1.59 (tq, J₁=7.81 Hz, J₂=7.42 Hz, 2H, CH₂(11)), 1.85 (t,J=2.34 Hz, 3H, CH₃(18)), 2.50 (m, 2H, CH₂(10)), 3.14 (t, J=8.59 Hz, 2H,CH₂(7)), 4.14 (q, J=2.34 Hz, 2H, CH₂(15)), 4.53 (s, 2H, CH₂(13)), 4.53(t, J =8.59 Hz, 2H, CH₂(8)), 6.94 (s, 2H, Ar—CH(4, 6)).

¹³C NMR (100 MHz, CDCl₃) (EN 16-46/2): δ=3.44 (CH₃(18)), 13.63(CH₃(12)), 24.84 (CH₂(11)), 29.66 (CH₂), 37.29 (CH₂), 57.72 (CH₂(15)),66.28 (CH₂(13)), 71.08 (CH₂(8)), 75.13 (C(17)), 82.21 (C(16)), 118.47(Ar—C(5)), 124.30 (Ar—CH), 126.64 (Ar—C(3)), 127.91 (Ar—CH), 134.50(Ar—C(1)), 156.16 (Ar—C(2)).

GC-MS (EN 16-46/1) (El) m/z (%): 244 (93) [M+], 215 (42), 189 (35), 175(100), 161 (43), 147 (85), 133 (37), 115 (16), 91 (21).

Example 8 Synthesis of5-n-propyl-7-((prop-2-ynyloxy)methyl)-2,3-dihydrobenzofuran

Following the same procedure described in Example 7b), but starting from45.3 g (0.28 mol) of 5-n-propyl-2,3-dihydrobenzofuran, 15.0 g (0.50 mol)of paraformaldehyde (purity 96.2%) and 140 g (1.42 mol) of HCl 37%, 15.7g (0.28 mol) of propargyl alcohol and 11.3 g (0.28 mol) of solid sodiumhydroxide, 28.2 g of an oil product was obtained after distillation at117°-120° C./20 Pa, whose NMR (¹H and ¹³C) and GC/MS analyses conformedto the structure.

¹H NMR (400 MHz, CDCl₃) (EN 16-47/4): δ=0.92 (t, 3H, J=7.42 Hz,CH₃(12)), 1.59 (tq, J₁=7.81 Hz, J₂=7.42 Hz, 2H, CH₂(11)), 2.44 (t,J=2.34 Hz, 1H, CH₃(17)), 2.50 (m, 2H, CH₂(10)), 3.15 (t, J=8.59 Hz, 2H,CH₂(7)), 4.18 (d, J=2.34 Hz, 2H, CH₂(15)), 4.54 (t, J=8.59 Hz, 2H,CH₂(8)), 4.56 (s, 2H, CH₂(13)), 6.94 (s, 1H, Ar—CH), 6.95 (s, 1H,Ar—CH).

¹³C NMR (100 MHz, CDCl₃) (EN 16-47/4): δ=13.67 (CH₃(12)), 24.87(CH₂(11)), 29.69 (CH₂), 37.31 (CH₂), 57.07 (CH₂(15)), 66.44 (CH₂(13)),71.15 (CH₂(8)), 74.33 (CH(17)), 79.74 (C(16)), 118.10 (Ar—C(5)), 124.55(Ar—CH), 126.79 (Ar—C(3)), 128.08 (Ar—CH), 134.60 (Ar—C(1)), 156.30(Ar—C(2)).

GC-MS (EN 16-47/1) (El) m/z (%): 230 (76) [M+], 201 (100), 190 (6), 175(40), 161 (32), 147 (46), 133 (15), 115 (15), 91 (15).

Example 9

Inhibition of Oxidase Enzymes by the Synergists in Bemisia tabaci

Ability of the compounds of the invention to inhibit oxidative enzymes(P450), a major mechanism conferring resistance to xenobiotics, wasmeasured using recombinant enzymes corresponding to CYPCM1 from Bemisiatabaci.

The following synergists were tested in comparison with piperonylbutoxide (PBO):

CYP6CM1

Substrate used was 7-ethoxycoumarin for inhibition assays as describedby Ulrich and Weber (1972) and adapted to microplate format as describedby De Sousa et al. (1995). This method had successfully been usedpreviously to characterise inhibition by some piperonyl butoxideanalogues against microsomal preparations from whole insects (Moores etal. 2009)

For inhibition assays, stock solutions of the compounds of Examples 1-9(10 mM) were prepared in acetone. Diluted recombinant enzyme (50 μL) wasmixed with 3 μL of the above mentioned compound stock solutions, withacetone only used as a control. After 10 min incubation at roomtemperature, 80 μL of 0.125 mM 7- ethoxycoumarin was added, followed by10 μL 9.6 mM NADPH (nicotinamide adenine dinucleotide phosphate) in 0.1M sodium phosphate, pH 7.8, and O-deethylation activity monitored asabove. A PBO solution (10 mM) was prepared in the same way as acomparison.

The results are reported in the Table 1 below:

TABLE 1 Bemisia tabaci CYPCM1 percentage of activity remaining Compound% activity remaining sem Compound of Example 2 27.49 1.77 Compound ofExample 3 3.16 1.85 Compound of Example 4 39.22 2.12 Compound of Example5 87.62 4.76 Compound of Example 6 61.16 4.61 Compound of Example 717.92 1.06 Compound of Example 8 86.22 4.10 PBO 106.49 4.50

The compounds of Examples 2-8 therefore show an inhibition activitybetter than PBO being the percentage of the remaining activity of theenzyme less when the synergists of the invention were used instead ofusing PBO.

Example 10

Inhibition of Esterasenzymes by Synergists in Myzus persicae

Inhibition of esterase activity cannot be measured by simplecolourimetric assays using routine model substrates, as the synergistdoes not bind at the active site (Philippou et al., 2013). It wasenvisaged, therefore, that the ‘esterase intereference assay’ (Khot etal., 2008) would be utilised for the purified esterases from aphids.Various esterase substrates were assessed to find one suitable ofmonitoring inhibition in an insect homogenate. The Myzus persicaeresistance associated esterase, FE4, was used.

FE4

Initially the esterase interference assay was carried out, as being the‘absolute’ protocol for characterizing interactions between thecompounds of Example 1-9 and FE4. However, since this is a protractedmethod, a selection of products already reported in the literature wereused to compare the interference assay and the use of a model substrate.

From the literature (Philippou et al., 2013) it is known that 1-naphthylacetate is not suitable for this assay. Instead, 4-nitrophenyl acetatewas used. A 10 mM pNA stock was prepared in acetone and added to 0.02 Mphosphate buffer pH 7.0 (final concentration 2 mM). The comparison wasmade with 6 PBO analogues of variable efficacy.

The result of this relatively high-throughput method was found to rankthe products identically to the interference assay, so this method wasused for further analysis of FE4 interactions.

For the assay 10 μL of purified FE4 was diluted to a total volume of 50μL by the addition of 0.02 M phosphate buffer, pH 7.0 in individualwells of a microplate (maxisorb, NUNC). To each well, 2.5 μL of 10 mM ofthe compound of Example 1 and of Example 2 in acetone was added andincubated for 10 mins, with acetone only used as a control. Followingincubation, 100 μL of 0.02 phosphate buffer, pH 7.0 and 100 μL of 2 mM4-nitrophenyl acetate was added (final volume in well 250 μL, finalsubstrate concentration 0.8 mM). Enzyme activity was read at 405 nm in aSpectramax Tmax for 5 min, with readings taken every 5 secs. The rate(mOD min⁻¹) was calculated by the integrated software, Softmax Prov.5.4. A PBO solution (10 mM) was prepared in the same way as acomparison.

The results of the percentage of the activity remaining are reported inthe Table 2 below.

TABLE 2 FE4 Myzus persicae esterases percentage of activity remainingCompound % activity remaining sem Compound of Example 1 26.16 0.45Compound of Example 2 35.44 1.00 Compound of Example 3 19.85 0.58Compound of Example 4 23.97 0.21 Compound of Example 5 18.38 0.62Compound of Example 6 29.8 0.70 Compound of Example 7 19.91 0.69Compound of Example 8 23.93 1.15 PBO 45.78 1.52

The compounds of Examples 1-8 therefore show an inhibition activitybetter than PBO being the percentage of the remaining activity of theenzyme less when the synergists of the invention were used instead ofusing PBO.

The invention claimed is:
 1. A compound of Formula (I)

wherein n is 1, R₁ is H or CH₃ and R₂ is a linear (C₃-C₆)alkyl.
 2. Thecompound of claim 1, wherein R₂ is n-butyl or n-hexyl.
 3. The compoundof claim 1, wherein the compound of Formula (I) is one of: 5-n-hexyl-7-((prop-2-ynyloxy)methyl)-2,3-dihydrobenzofuran,5-n-hexyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran,5-n-butyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran,5-n-butyl-7-((prop-2-ynyloxy)methyl)-2,3-dihydrobenzofuran,5-n-propyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran, and5-n-propyl-7-((prop-2-ynyloxy)methyl)-2,3-dihydrobenzofuran.
 4. Thecompound of claim 3, wherein the compound is one of:5-n-hexyl-7-((prop-2-ynyloxy)methyl)-2,3-dihydrobenzofuran,5-n-hexyl-7-((but-2-ynyloxy)methyl)- 2,3-dihydrobenzofuran,5-n-butyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran,5-n-butyl-7-((but-2-ynyloxy)methyl)- 2,3-dihydrobenzofuran, and5-n-propyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran.
 5. Thecompound of claim 4, wherein the compound is one of5-n-butyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran, and5-n-propyl-7-((but-2-ynyloxy)methyl)-2,3-dihydrobenzofuran.
 6. Aninsecticide composition comprising at least one insecticide activeingredient and at least one compound of Formula (I) according to claim 1to insects directly and/or a biotope thereof.
 7. An insecticideformulation comprising the insecticide composition of claim 6 and acarrier.
 8. A non-therapeutic method for killing insects in closed andopen environments, said method comprising the step of applying theinsecticide composition of claim
 6. 9. The method of claim 8 for killinginsects in agriculture.
 10. The method of claim 8, wherein the insectsare selected from the order insect group consisting of Hemiptera,Diptera, Blattaria, Thysanoptera, Isoptera, and Acarina.
 11. Atherapeutic method for treating pediculosis in humans, said methodcomprising applying the insecticide composition of claim
 6. 12. Atherapeutic method for treating non-systemic or systemic parasites andinsects in non-human mammals comprising applying the pesticidecomposition of claim 6 systemically or non-systemically to non-humanmammals.